CDG e Conferences & Workshops

European Medical Device Regulations Tighter than US

Introduction to Medical Device Regulations: EU

A Whitepaper and Workshop by Nancy J Stark, PhD
Thursday, 1 July 2010, 11 AM Central; or OnDemand soon after.
Reading someone else's copy? Opt-in for whitepapers to get your own.

The fundamentals of EU regulations are evolving rapidly....
In this whitepaper I want to discuss the fundamentals of medical device regulations in the European Union with the goal of determining whether or not a clinical study is necessary in order to obtain certification and CE Mark. This is an introductory discussion intended for those who are new to the medical device industry.

The fundamentals of medical device regulations in the United States are discussed in a companion whitepaper and workshop. The companion US workshop is available Wednesday, 30 June 2010, 11 AM Central and on OnDemand soon after.

Regulation by European Medicines Agency?
In 2008, medical device regulation in Europe was fragmented, disorganized, and hard to understand. All 27 States has imposed their own unique positions on the law, making regulation an impossible puzzle.

The 2008 system of regulation left the following issues wanting:
[1] 80 Notified Bodies from 27 Member States resulted in variable enforcement and inspection.
[2] Three main Directives and six implementing or modifying Directives were hard to follow.
[3] IVDs were not risk-based classified.
[4] 'Quasi' devices such as lip fillers and wrinkle fillers were not regulated.
[5] Notified Bodies were not transparent, did not share information with each other.
[6] Notified Bodies didn't communicate the Competent Authorities.
[7] Manufacturers openly shopped for Notified Bodies that would give easy inspections (forum shopping.)
[8] There was wide variation in vigilance reporting from State to State.
[9] The incidence of vigilance reports was considerably lower than in the US or Japan.
[10] There was no centralized registration system for devices; even Competent Authorities don't know what is being sold.
[11] NBs do not inspect foreign manufacturers with same rigor as EU manufacturers.
[12] Devices for export were not regulated.

Intrigue at the European Commission
But while the European device industry was dragging its feet, resisting changes to ISO 14155 (2003), and generally working to maintain the status quo, a coup was cooking in the kitchen. Suddenly one day, the European Commission proposed creation of a Medical Device Committee within the European Medicines Agency (EMEA). The proposal would have given the EMEA, as possibilities, the following powers:
[1] Consolidation of all existing nine Directives into one.
[2] Regulation of medical devices made up wholly of non-viable human cells or tissues or derivatives.
[3] Imposition of sanctions and penalties on Notified Bodies who failed to act properly.
[4] Create an automatic link between invoking the Safeguard Clause and withdrawal of certification.
[5] Accreditation system for Notified Bodies.
[6] Public input into approval of high-risk devices.
[7] Mandate institution and caregiver vigilance reporting.
[8] Exchange vigilance report globally.
[9] Strengthen Commission's authority for post-market surveillance.
[10] Medical Device Committee to provide opinions on classification of borderline devices.
[11] Incorporate GHTF guidances as much as possible into new regulatory framework.

Quick action by device industry
The device industry suddenly woke up and was quick to act. This ISO 14155 Working Group resumed activity and is finally getting a new standard out—a standard harmonized with the Medical Device Directive as much as the intended International Conference on Harmonization Good Clinical Practice. The Notified Bodies have begun to coordinate their activities and are diligently inspecting technical files for the presence of clinical evaluation reports. The existing regulatory framework was not changed.

If you are new to Europe
If you are new to European regulations, the story above probably sounded like a soap opera. But read on, and take the workshop, and it will all make sense to you.

The European Union
Europe was not always a union, and most would argue that it isn't one yet today. It is a collection of individual states (countries) whose integration is driven by economic aims, not political ones. The upshot is that industry and regulators are often at odds with each other: industry pushing for a common regulatory system across the union while regulators strive to retain opacity and independence.

An economic union is a collection of peoples and geographic areas that share a common market through the free movement of goods, services, jobs, and people; and who present a common economic face to the world: they share a common currency, have common import and export tariffs, a common tax rate, and common fiscal and economic policies. If you've shopped in Europe you know that they are not quite there yet. The price tag on a sweater lists the price in Euros, true, but there is a different price for France, Germany, Italy, and every other country.

In 1992 there were 15 member states in the union, consisting of Western, economically developed countries. Today there are 27 member states. In 2004, the EU saw its biggest single enlargement when Malta, Cyprus, Slovenia, Estonia, Latvia, Lithuania, Poland, the Czech Republic, Slovak Republic, and Hungary were admitted as members.

The government, located in Brussels, consists of a Parliament, Council, and Commission. The Council sets the general direction and priorities of the Union. The Commission proposes laws (i.e. directives) consistent with the priorities set by the Council. The Parliament and Council jointly approve the directives, which are then issued as law by the Council.

 
The New Approach
When Europe sought to set up a review and approval system for medical devices, they wanted to take advantage of existing governmental institutions. Since the 'old' way to set up a government was to create a entirely new infrastructure, the idea of using what was already there was called the New Approach.

In the New Approach, the European Council issues directives (laws) to govern the sale of medical devices. There are three directives of particular concern to us:
[1] Active Implantable Medical Device Directive (AIMD) 1990-385-EEC.
[2] Medical Device Directive (MDD) 1993-42-EEC.
[3] In Vitro Diagnostic Directive (IVD) 1998-79-EC.

The Standards Body (ISO or CEN), using a committee of experts from industry, investigative sites, and regulators, publishes new standards that are incorporated into directives and become de facto regulation. The standard of concern for medical device trials is ISO/FDIS 14155 "Clinical investigation of medical devices for human subjects—good clinical practice" (2010) and it will be incorporated into Annex 7 and Annex X of the AIMD and MDD, respectively. The standard does not apply to in vitro diagnostic devices.

The Regulatory Body or Competent Authority, usually the department of health and welfare for that country, is responsible to implement directives, regulate clinical research, appoint Ethics Committees and Notified Bodies, and approve the initiation of medical device trials. Most countries have only one Competent Authority, but Germany has more than 40, one from each county.

The various Ethics Committees located within a member state are often appointed regionally and may be structured in a tiered approach. Some Ethics Committees give only opinions, but not approval, regarding a clinical trial. The Ethics Committees in Germany have a close association with the professional medical society.

Finally, the Notified Body, an independent accredited body of experts, is authorized by the Regulatory Body to enforce regulations, review clinical trial results, and inspect a manufacturer's quality management system in application for certification, CE Marking, and approval for sale of a medical device. A country may have as many Notified Bodies as it wants; Germany has sixteen.

Device classification
Devices are as diverse as toothbrushes to heart valves, or sunlamps to breast implants. It would be unreasonable to regulate all devices the same way. Wrapping your mind around a country's approach to device regulation is challenging. The point of entry is to first learn how that country classifies devices. All countries classify devices by history or risk, and then regulate the devices differently depending on its classification. In Europe, devices are AIMD, MDD Class I, MDD Class IIa, MDD Class IIb, MDD Class III, or IVD.

[1] Active implantable medical devices: are both implanted and energy requiring.
[2] MDD Class I: non-invasive devices that do not contact blood or body tissues.
[3] MDD Class IIa: short-term use devices that channel blood or body liquids or connect to higher-class devices, also dental devices.
[4] MDD Class IIb: long-term use devices which contact breached skin, supply energy, deliver drugs, monitor vital processes, contraceptives, disinfectants, or blood bags.
[5] MDD Class III: long-term invasive devices which are heart or central circulatory system contacting, central nervous system contacting, biodegradable, drug-device combinations, implantables, or based on animal tissues.

You can consult the European Commission medical devices guidance document MEDDEV 2.4/1 Rev.8 July 2001 for details of classification. Europe is fundamentally different than the States in its classification strategy: there are a series of eighteen rules to follow, which allow you to determine the classification by process of elimination. It is a tidier and simpler approach than the States, but then Europe had the benefit of studying the strengths and weaknesses of our system before developing their own.

CE Mark now, review later
The question we are trying to answer with all of this is whether or not you need to do a clinical trial in order to get Notified Body certification of your quality management system, which gives you authority to affix a CE Mark to our device. But you have a few more variables to work out first, before you can be sure.

Conformity Assessment
The next step is to determine which of eight possible pathways you want to follow in order to assess conformity of your manufacturing process to the specifications set forth in your quality management system. Putting it simply, you: [1] select a Notified Body, [2] have the Notified Body inspect your quality management system and issue you a certificate, [3] design a device and complete a technical file, [4] give yourself a CE Mark, sign your Declaration of Conformity, and start selling, and then [5] the Notified Body reviews your Technical Files at their next visit to see if they agree with your decision.

Do you need a new clinical trial?
Finally, for every medical device you prepare a clinical evaluation report. The evaluation of clinical data consists of three modules and a summary report:
[1] review of published literature to assess safety and performance.
[2] review of any related clinical studies you may have sponsored to assess safety and performance.
[3] review of any related complaints to determine if the quality management system is adequate to support an argument of safety and performance.
[4] summary report to present conclusions.

The results of the clinical evaluation report should lead you to a decision as to whether existing data are sufficient to support an argument of safety and performance for the device's intended use, or if new, additional clinical data are necessary. I discussed the details of how to perform a clinical evaluation report in a whitepaper published last April.

If you liked the whitepaper, take the workshop
The objective of the workshop is to learn the basics of European regulations and how to determine if you need a clinical study in order to get market your device. Sign up at registration.

This is an introductory workshop and focuses on European regulations. A complimentary workshop focusing on US regulations is also available.

You will receive, we will discuss
[x] PowerPoint slides.
[x] A two-hour presentation.
[x] Discussion of the Directives.
[x] Meaning of Essential Requirements.
[x] Medical device classification in Europe.
[x] Relationship between standards and regulations.
[x] Supporting handouts, flowcharts, and graphic presentations.
[x] A complimentary US/ISO Adverse Event mousepad/notepad (by mail).
[x] A 30-minute quiz to reinforce your learning experience.
[x] CEUs and certificate of attendance.

Who should attend
[x] Anyone new to medical devices.
[x] Anyone new to medical device clinical trials.
[x] Anyone needing to know about medical device regulations.

Presenter
Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration for US Workshop
The three-hour workshop will be presented on Wednesday, 30 June 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Date, time, registration for EU Workshop
The two-hour workshop will be presented on Wednesday, 1 July 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

Introduction to Medical Device Regulation in the US

The fundamentals of US Regulations are unlikely to change...

A Whitepaper and Workshop by Nancy J Stark, PhD
Tuesday, 06 July 2010, 10 am Central; or OnDemand soon after.
Reading someone else's copy? Opt-in for whitepapers to get your own.

In this whitepaper I want to discuss the fundamentals of medical device regulations in the United States with the goal of determining whether or not a clinical study is necessary in order to obtain FDA clearance. This is an introductory discussion intended for those who are new to the medical device industry.

The fundamentals of medical device regulations in the European Union are discussed in a companion whitepaper and workshop. The companion EU workshop is available Thursday, 1 July 2010, 11 AM Central and on OnDemand soon after.

Food, Drug and Cosmetic Act
In the States, medical devices are regulated by the Food, Drug and Cosmetic Act. Then called the Food and Drug Act, it was the first piece of legislation to result from investigative journalism, namely a novel titled "The Jungle" by Upton Sinclair. Sinclair described the filthy conditions of pre-WWI Chicago stockyards and the contamination of our food supply. You can still buy the book, a heart-wrenching, stomach-punching period piece, for $5.95. Sinclair published The Jungle in 1906, and the Food and Drug Act was passed in 1923. In 1933, as part of the 'New Deal', legislation was introduced to expand the Act to cover medical devices; the expansion passed in 1938.

Adulteration and Misbranding
The Food and Drug Act set forth two simple concepts that still govern medical devices today—adulteration and misbranding. Adulteration speaks to the issue of filth, contamination, or toxins being present in or on a medical device. For example, some devices use water during the manufacturing process. The water must be pyrogen free or the finished device will probably be contaminated with pyrogenic material. Pyrogens cause an intense fever spike when they get into the body—an unwanted medical occurrence for any device.

Misbranding speaks to the issue of making false or misleading statements. For example, if I say the device can be used to reduce an HIV viral load, but it not cleared for this indication, it is misbranded. If I say it is sharp enough for a surgical cut and it isn't, it is misbranded.

If I say the knife is sterile, and it isn't, it is both adulterated and misbranded.

Chapter V: Drugs and Devices
Chapter V of the Act deals with drugs and devices. This is where you find the relevant sections of the Act, itself. Follow the link to Chapter V if you want to read more about any of the topics.

Regulations
If you look at the Act, you'll see that it is general; written to last over time and lacking in the specifics that enable day-to-day implementation. The specifics are left to the regulations, which are promulgated by the Food and Drug Agency (FDA). Regulations are rules which have the force of law. They are first published as proposed rules and are open to public comment. Some comments are accepted, other rejected. When the regulation is first published as a final rule it appears in the Federal Register along with a summary of the comments and FDA's responses and explanations, called the preamble. Preamble's have legal standing and are worth your while to read and understand.

Once a year the regulations and associated amendments, but not the preambles, are published in the Code of Federal Regulations, Title 21. 21 CFR, Parts 1-99 are regulations that apply to devices, drugs, and biologics. Parts 800-1299 are regulations that apply only to devices. If you work in clinical research, you should become intimate with Parts 50, 54, 56, 812, and 814.

Device Classification—point of entry
Devices are as diverse as toothbrushes to heart valves, or sunlamps to breast implants. It would be unreasonable to regulate all devices the same way. Wrapping your mind around a country's approach to device regulation is challenging. The point of entry is to first learn how that country classifies devices. All countries classify devices by history or risk, and then regulate the devices differently depending on its classification. In the States, devices are classified as Class I—General Controls, Class II—Special Controls, and Class III—Premarket Approval.

Class I devices have a reasonable assurance of safety and effectiveness if manufactured under current good manufacturing practices. Approximately 74% of the Class I devices are exempt from the premarket notification process (i.e., 510k clearance). These exemptions are listed in the classification regulations of 21 CFR and have been collected together in the Medical Device Exemptions document.

Class II devices have a reasonable assurance of safety and effectiveness if manufactured under current good manufacturing practices and whatever special controls deemed necessary by FDA, such as performance standards, postmarket surveillance, patient registries, guidance documents, or evidence of efficacy from a well-controlled clinical study.

Class III devices are devices purported or represented to be for a use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health and there is not sufficient information to establish a performance standard for reasonable assurance of safety and effectiveness.

Intended Use, Indications for Use
Let's say you are developing a device that is new to your company. Your first concern is to identify its classification, because all other regulatory requirements will stem from there. But the classification will depend on a few more variables you'll have to fix before you can make that determination.

Intended Use
The first decision is to decide on the intended use for the device. In a market-driven company we probably have an indication (customer need) looking for a device, but in technology-driven companies it is common to have a device looking for an intended use. Think in terms of an active verb: do you intend to ablate tissue, vibrate cells, stimulate neurons, fix body parts, take images, or measure impedance? Deciding on your intended use for a device is the first step in determining its classification.

Indication for use
The next step is to decide on the disease or condition you plan to diagnose, cure, mitigate, treat, or prevent. Think in terms of diseases and conditions to which the intended use can be applied. You might ablate tissue in order to prevent tumor growth, you might vibrate cells in order to intercept a seizure, you might fix the spine in order to prevent curvature or treat scoliosis, and so on. The intended use may have many applications in medicine, i.e., there may be many diseases or conditions to which it can be applied.

Some indications will cause your device to be classified higher than other indications. For example, if you say your device will diagnose breast cancer it is going to be a Class III device, but if you say it is a adjunct test for the diagnosis of breast cancer it will be a Class II device. If you indicate a device that exposes to body to magnetic waves as a treatment for HIV it is going to be a Class III device, but if you indicate that magnetic waves help activate the immune system to viral load, it may be a Class II de novo.

Think of your device as consisting of two parts: 1) the physical device, and 2) its indications for use. If you are a start-up firm, choose an indication for use for which it is easy and inexpensive to get FDA clearance. Go after the harder, and more profitable, indications for use after you have experience and cash flow.

How to determine classification
Go to FDA's product classification database and search for a part of the device name or, if you know the device panel (medical specialty) to which your device belongs, go directly to the listing for that panel and identify your device and the corresponding regulation.

It may sound simple to find your device, but it isn't. The classification database does not have a fuzzy search engine; you will find only what you ask for. Suppose you have a radio-frequency ablation device. A search for "radio frequency ablation" turns up nothing, a search for "RF ablation" turns up nothing, finally a search for "ablation" brings up twelve records: one is a mapping instrument to plan the ablation, four are for cardiac atrial flutter, one is for endometrial ablation, one for urological ablation, one—for treatment of varicose veins—is grandfathered in as a pre-amendment device, two are low-energy devices for general soft tissue ablation, one uses ultrasound as a high energy source, and one uses liquid nitrogen for cosmetic surgery (like removing moles).

It is useful to note is that the primary tissue (think disease or condition) being ablated dictates which device panel reviews the device, and the energy intensity (high or low) as well as the newness of the technology dictates its classification. Unfortunately, we still don't know how our RF-ablation device is classified.

Device classification panels
FDA has classified and described over 1,700 distinct types of devices and organized them in the CFR into 16 medical specialty "panels". For each of the devices classified by the FDA the CFR gives a general description including the intended use, the class to which the device belongs (i.e., Class I, II, or III), and information about marketing requirements. Your device will presumably meet the definition in a classification regulation contained in 21 CFR 862-892.

A search for "RF" in the product classification database is more useful. We find seven devices, one is a Class III device for RF/microwave hyperthermia for cancer treatment—sounds like a good match and finally we know the class and regulatory status of our device and indication.

Let's discuss the product code. The product code, together with the product name, uniquely identifies a category of devices for FDA and is a useful way to find related products. If you go to the PMA database and search on the product code LOC, you will find 27 PMA submissions or amendments. Here you will find some useful information, such as the manufacturer of the devices, when they received clearance, location of the manufacturing facilities, which advisory panel reviewed the PMA, and more.

Notice the absence of a Regulation Number? While FDA may say: "Your device should meet the definition in a classification regulation contained in 21 CFR 862-892," the truth is that it can take years before FDA assigns a regulation number to a new product category.

510(k) or PMA
The point of classification is to determine the pathway to FDA clearance. You don't have a choice in the matter, unless you want to revise the indications for use. To summarize it simply:
[ ] Class I—74% are exempt from requiring FDA clearance, the remainder need a 510(k).
[ ] Class II—requires a 510(k), which is a type of FDA submission in which you argue that your device is substantially equivalent to another device which was on the market prior to May 28, 1976.
[ ] Class II de novo 510(k)—a Class III device that is a new technology of low risk; for example exposing the hands to a magnetic field for immune system stimulation. New technologies are automatically Class III devices, but the manufacturer can petition FDA for a down-classification to Class II. The difference is the 510(k) requires de novo (from the beginning) evidence of safety and effectiveness, rather than evidence of substantial equivalence, because there is nothing to be equivalent to.
[ ] Class III—requires pre-market approval (PMA).

The BIG question—do you need a clinical trial?
The question we've been trying to answer with all of this is whether or not we need to do a clinical trial in order to get FDA clearance. The answer is:
[ ] No, if you have a Class I device.
[ ] Maybe, if you have a Class II device. About 10% of 510(k)s require clinical trials in order to support the argument of substantial equivalence.
[ ] Yes, if you have a Class II de novo device.
[ ] Yes, if you have a Class III, PMA device.

If you liked the whitepaper, take the workshop
The objective of the workshop is to learn the basics of FDA device regulations and how to determine if you need a clinical study in order to get FDA clearance. Sign up at registration.

This is an introductory workshop and focuses on US regulations. A complimentary workshop focusing on European regulations is also available.

You will receive, we wil discuss
[x] PowerPoint slides.
[x] A three-hour presentation.
[x] Discussion of the types of 510(k).
[x] Difference between 510(k)s and PMAs.
[x] How to take advantage of the Mohan memorandum.
[x] Distinction between guidance documents and standards.
[x] Supporting handouts, flowcharts, and graphic presentations.
[x] A complimentary US/ISO Adverse Event mousepad/notepad (by mail).
[x] A 30-minute quiz to reinforce your learning experience.
[x] CEUs and certificate of attendance.

Who should attend
[x] Anyone new to medical devices.
[x] Anyone new to medical device clinical trials.
[x] Anyone needing to know about medical device regulations.

Presenter
Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration for US Workshop
The three-hour workshop will be presented on Tuesday, 6 July 2010, at 10:00 am Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Date, time, registration for EU Workshop
The three-hour workshop will be presented on Wednesday, 1 July 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Learn the world discount
Register for both workshops and get $100 off! Enter the coupon code SUMMER at check-out.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

Introduction to Medical Device Regulations: EU

A Whitepaper and Workshop by Nancy J Stark, PhD
Thursday, 1 July 2010, 11 AM Central; or OnDemand soon after.
Reading someone else's copy? Opt-in for whitepapers to get your own.

The fundamentals of EU regulations are evolving rapidly....
In this whitepaper I want to discuss the fundamentals of medical device regulations in the European Union with the goal of determining whether or not a clinical study is necessary in order to obtain certification and CE Mark. This is an introductory discussion intended for those who are new to the medical device industry.

The fundamentals of medical device regulations in the United States are discussed in a companion whitepaper and workshop. The companion US workshop is available Wednesday, 30 June 2010, 11 AM Central and on OnDemand soon after.

The European Union
Europe was not always a union, and most would argue that it isn't one yet today. It is a collection of individual states (countries) whose integration is driven by economic aims, not political ones. The upshot is that industry and regulators are often at odds with each other: industry pushing for a common regulatory system across the union while regulators strive to retain opacity and independence.

An economic union is a collection of peoples and geographic areas that share a common market through the free movement of goods, services, jobs, and people; and who present a common economic face to the world: they share a common currency, have common import and export tariffs, a common tax rate, and common fiscal and economic policies. If you've shopped in Europe you know that they are not quite there yet. The price tag on a sweater lists the price in Euros, true, but there is a different price for France, Germany, Italy, and every other country.

In 1992 there were 15 member states in the union, consisting of Western, economically developed countries. Today there are 27 member states. In 2004, the EU saw its biggest single enlargement when Malta, Cyprus, Slovenia, Estonia, Latvia, Lithuania, Poland, the Czech Republic, Slovak Republic, and Hungary were admitted as members.

The government, located in Brussels, consists of a Parliament, Council, and Commission. The Council sets the general direction and priorities of the Union. The Commission proposes laws (i.e. directives) consistent with the priorities set by the Council. The Parliament and Council jointly approve the directives, which are then issued as law by the Council.

 

The New Approach
When Europe sought to set up a review and approval system for medical devices, they wanted to take advantage of existing governmental institutions. Since the 'old' way to set up a government was to create a entirely new infrastructure, the idea of using what was already there was called the New Approach.

In the New Approach, the European Council issues directives (laws) to govern the sale of medical devices. There are three directives of particular concern to us:
[1] Active Implantable Medical Device Directive (AIMD) 1990-385-EEC.
[2] Medical Device Directive (MDD) 1993-42-EEC.
[3] In Vitro Diagnostic Directive (IVD) 1998-79-EC.

The Standards Body (ISO or CEN), using a committee of experts from industry, investigative sites, and regulators, publishes new standards that are incorporated into directives and become de facto regulation. The standard of concern for medical device trials is ISO/FDIS 14155 "Clinical investigation of medical devices for human subjects—good clinical practice" (2010) and it will be incorporated into Annex 7 and Annex X of the AIMD and MDD, respectively. The standard does not apply to in vitro diagnostic devices.

The Regulatory Body or Competent Authority, usually the department of health and welfare for that country, is responsible to implement directives, regulate clinical research, appoint Ethics Committees and Notified Bodies, and approve the initiation of medical device trials. Most countries have only one Competent Authority, but Germany has more than 40, one from each county.

The various Ethics Committees located within a member state are often appointed regionally and may be structured in a tiered approach. Some Ethics Committees give only opinions, but not approval, regarding a clinical trial. The Ethics Committees in Germany have a close association with the professional medical society.

Finally, the Notified Body, an independent accredited body of experts, is authorized by the Regulatory Body to enforce regulations, review clinical trial results, and inspect a manufacturer's quality management system in application for certification, CE Marking, and approval for sale of a medical device. A country may have as many Notified Bodies as it wants; Germany has sixteen.

Device classification
Devices are as diverse as toothbrushes to heart valves, or sunlamps to breast implants. It would be unreasonable to regulate all devices the same way. Wrapping your mind around a country's approach to device regulation is challenging. The point of entry is to first learn how that country classifies devices. All countries classify devices by history or risk, and then regulate the devices differently depending on its classification. In Europe, devices are AIMD, MDD Class I, MDD Class IIa, MDD Class IIb, MDD Class III, or IVD.

[1] Active implantable medical devices: are both implanted and energy requiring.
[2] MDD Class I: non-invasive devices that do not contact blood or body tissues.
[3] MDD Class IIa: short-term use devices that channel blood or body liquids or connect to higher-class devices, also dental devices.
[4] MDD Class IIb: long-term use devices which contact breached skin, supply energy, deliver drugs, monitor vital processes, contraceptives, disinfectants, or blood bags.
[5] MDD Class III: long-term invasive devices which are heart or central circulatory system contacting, central nervous system contacting, biodegradable, drug-device combinations, implantables, or based on animal tissues.

You can consult the European Commission medical devices guidance document MEDDEV 2.4/1 Rev.8 July 2001 for details of classification. Europe is fundamentally different than the States in its classification strategy: there are a series of eighteen rules to follow, which allow you to determine the classification by process of elimination. It is a tidier and simpler approach than the States, but then Europe had the benefit of studying the strengths and weaknesses of our system before developing their own.

The BIG question—do you need a clinical trial?
The question we've been trying to answer with all of this is whether or not you need to do a clinical trial in order to get Notified Body certification of your quality management system, which gives you authority to affix a CE Mark to our device. But you have a few more variables to work out first, before you can be sure.

 

Conformity Assessment
The next step is to determine which of eight possible pathways you want to follow in order to assess conformity of your manufacturing process to the specifications set forth in your quality management system. Putting it simply, you: [1] select a Notified Body, [2] have the Notified Body inspect your quality management system and issue you a certificate, [3] design a device and complete a technical file, [4] give yourself a CE Mark, sign your Declaration of Conformity, and start selling, and then [5] the Notified Body reviews your Technical Files at their next visit to see if they agree with your decision.

Clinical Evaluation Reports have the answer
Finally, you prepare a clinical evaluation report for the device. The clinical evaluation report consists of three modules:
[1] review of published literature to assess safety and performance.
[2] review of any related clinical studies you may have sponsored to assess safety and performance.
[3] review of any related complaints to determine if the quality management system is adequate to support an argument of safety and performance.

The results of the clinical evaluation report should lead you to a decision as to whether existing data are sufficient to support an argument of safety and performance for the device's intended use, or if new, additional clinical data are necessary. I discussed the details of how to perform a clinical evaluation report in a whitepaper published last April.

If you liked the whitepaper, take the workshop
The objective of the workshop is to learn the basics of European regulations and how to determine if you need a clinical study in order to get market your device. Sign up at registration.

This is an introductory workshop and focuses on European regulations. A complimentary workshop focusing on US regulations is also available.

You will receive, we will discuss
[x] PowerPoint slides.
[x] A two-hour presentation.
[x] Discussion of the Directives.
[x] Meaning of Essential Requirements.
[x] Medical device classification in Europe.
[x] Relationship between standards and regulations.
[x] Supporting handouts, flowcharts, and graphic presentations.
[x] A complimentary US/ISO Adverse Event mousepad/notepad (by mail).
[x] A 30-minute quiz to reinforce your learning experience.
[x] CEUs and certificate of attendance.

Who should attend
[x] Anyone new to medical devices.
[x] Anyone new to medical device clinical trials.
[x] Anyone needing to know about medical device regulations.

Presenter
Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration for US Workshop
The three-hour workshop will be presented on Wednesday, 30 June 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Date, time, registration for EU Workshop
The two-hour workshop will be presented on Wednesday, 1 July 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Learn the world discount
Register for both workshops and get $100 off! Enter the coupon code SUMMER at check-out.

Best regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

ISO/FDIS 14155 (2010) and Clinical Evaluations

Clinical evaluations justify design of clinical investigations A Whitepaper by Nancy J Stark, PhD.

Today I want to discuss the role that clinical evaluations will play in justifying the implementation and design of device clinical trials once the 2010 ISO/DIS 14155 "Clinical investigations for medical devices in human subjects--good clinical practices" becomes a published standard. Over the past several months I've written extensively about clinical evaluation reports, but always within the context of obtaining or maintaining a CE Mark and quality system certification. What does the standard say? The ISO/DIS 14155 (2010) standard states: Clinical evaluations may be indication specific The intent of the standard is that a clinical evaluation report be prepared before any clinical trial begins. The results of the clinical evaluation report--performed with selected indications in mind--should lead naturally to the decision as to whether or not new clinical data are needed to confirm the safety and performance of the device, or that existing data are sufficient in and of themselves. Shades of the American system The idea of using existing data to support an argument of safety and performance (i.e., safety and efficacy) is not new to Americans. Although there is no literature review requirement for non-significant risk studies under the abbreviated IDE system, an extensive Report of Prior Investigations is required for every full IDE before FDA will grant approval to conduct a significant risk clinical trial. Part 812.20(b)(2) states: A sponsor shall submit "...a complete report of prior investigations of the device..." as part of the IDE application. GHTF SG5 is the guiding document The Global Harmonization Task Force (GHTF) Study Group 5 document "Clinical Evaluation" is the guiding light for preparing clinical evaluation reports. While you may choose to follow MEDDEV 2.7.1 Rev 3, the European (region specific) document couldn't be referenced in an international standard. The steps for preparing clinical evaluation reports to justify a clinical trial are the same as those for a clinical evaluation report for maintaining certification and CE Marking except that pre-clinical testing becomes an important part of the review. Briefly, the steps are: [1] Define the key questions. [2] Identify the databases to search (usually MedLine, Embase, MAUDE, and Cochrane). [3] Define scope of search and search strategies using a qualified information specialist. [4] Assess abstracts to identify articles for weighting. [5] Acquire full-texts of articles. [6] Read and weight the articles for relevance. [7] Weight the articles for statistical significance using a qualified biostatistician. [8] Review only those articles with the highest weightings; typically 6-8 articles per indication. [9] Review existing sponsored clinical investigations. [10] Review the risk management system. And additionally, [11] Review the pre-clinical and biocompatibility data. [12] Finalize the report, taking into account the four elements of: ----[b] existing clinical data from the literature, ----[c] data from existing clinical investigations sponsored by the manufacturer, ----[d] the risk management system, and ----[a] pre-clinical testing including bench, animal, and biocompatibility data. The clinical evaluation should lead you naturally to a decision as to whether a new clinical investigation is necessary and, if so, to its design. A shift in thinking The thinking is a little bit different than what I was trained to do. Perhaps erroneously, the default position was always to do a clinical investigation to demonstrate safety and efficacy in humans unless you could justify not doing one. But so many trials are being done today there is a critical shortage of subjects. The new (European) thinking is that a clinical investigation is only performed if existing literature data, existing clinical data, the risk management system, and pre-clinical data--taken together--cannot confirm the safety and performance of your device for a selected indication. Rephrase the indication As the manufacturer, you will have some choices in situations where new clinical trials are deemed necessary. If a study is too expensive for your corporate budget, you can probably rephrase the indication. For example, an indication for the prevention of epileptic seizures by early neurological intervention might require a different level of data than the abatement of epileptic seizures by neurological intervention triggered by the seizure itself. Or the relief of cancer pain might require a different level of data than the management of physical discomfort. Or a wrist support to heal carpal tunnel syndrome might require more data than a wrist support to stabilize the joint. Return on investment If the indication represents a large enough market size, the cost of the clinical trial may be justifiable. It's a simple enough exercise: estimate the cost of the clinical trial, estimate the profits from the new indication, and determine profit/loss over the next six months. Return on investment (ROI) = (estimated new profits - cost of trial)/(cost of trial); for example, the ROI for pediatric clinical trials ranged from -$8.9 million to +$507.9 million over six months. Many companies consider their estimated daily sales for a new indication and view every day the trial is delayed as a lost opportunity cost. Once the decision to implement the clinical trial is made by top management the pressure is on to get the trial underway and completed. CDG can help Clinical Device Group is poised to help you work through the process of evaluating existing data and justifying the design of a clinical trial. We have a vast network of professionals who are experts in biocompatibility, information technology, medical writing, clinical research, biostatistics, data management, market size estimation, cost estimation, scheduling and Gantt chart preparation, and regulatory submissions. Our experts are ready to: [1] Assess your pre-clinical and biocompatibility data, [2] Prepare a clinical evaluation report, [3] Suggest design variations for a clinical trial with larger or smaller sample sizes, depending the indication's wording, [4] Write or review your protocol, [5] Estimate the market size and profitability of the indication, [6] Estimate the cost of the clinical trial, [7] Calculate the return on investment, [8] Implement and monitor the trial, [9] Enter and manage the data, [10] Analyze the data to support or refute the indication, [11] Prepare the final trial report, [12] Prepare the regulatory submissions for product commercialization. Contact us Phone or email us at 773-489-5706 or cdginc@clinicaldevice.com.

Introduction to Medical Device Regulation: US

The fundamentals of US Regulations are unlikely to change...

A Whitepaper and Workshop by Nancy J Stark, PhD
Tuesday 6 July 2010, 10:00 AM Central; or OnDemand soon after.
Reading someone else's copy? Opt-in for whitepapers to get your own.

In this whitepaper I want to discuss the fundamentals of medical device regulations in the United States with the goal of determining whether or not a clinical study is necessary in order to obtain FDA clearance. This is an introductory discussion intended for those who are new to the medical device industry.

The fundamentals of medical device regulations in the European Union are discussed in a companion whitepaper and workshop. The companion EU workshop is available Thursday, 1 July 2010, 11 AM Central and on OnDemand soon after.

Food, Drug and Cosmetic Act
In the States, medical devices are regulated by the Food, Drug and Cosmetic Act. Then called the Food and Drug Act, it was the first piece of legislation to result from investigative journalism, namely a novel titled "The Jungle" by Upton Sinclair. Sinclair described the filthy conditions of pre-WWI Chicago stockyards and the contamination of our food supply. You can still buy the book, a heart-wrenching, stomach-punching period piece, for $5.95. Sinclair published The Jungle in 1906, and the Food and Drug Act was passed in 1923. In 1933, as part of the 'New Deal', legislation was introduced to expand the Act to cover medical devices; the expansion passed in 1938.

Adulteration and Misbranding
The Food and Drug Act set forth two simple concepts that still govern medical devices today—adulteration and misbranding. Adulteration speaks to the issue of filth, contamination, or toxins being present in or on a medical device. For example, some devices use water during the manufacturing process. The water must be pyrogen free or the finished device will probably be contaminated with pyrogenic material. Pyrogens cause an intense fever spike when they get into the body—an unwanted medical occurrence for any device.

Misbranding speaks to the issue of making false or misleading statements. For example, if I say the device can be used to reduce an HIV viral load, but it not cleared for this indication, it is misbranded. If I say it is sharp enough for a surgical cut and it isn't, it is misbranded.

If I say the knife is sterile, and it isn't, it is both adulterated and misbranded.

Chapter V: Drugs and Devices
Chapter V of the Act deals with drugs and devices. This is where you find the relevant sections of the Act, itself. Follow the link to Chapter V if you want to read more about any of the topics.

Regulations
If you look at the Act, you'll see that it is general; written to last over time and lacking in the specifics that enable day-to-day implementation. The specifics are left to the regulations, which are promulgated by the Food and Drug Agency (FDA). Regulations are rules which have the force of law. They are first published as proposed rules and are open to public comment. Some comments are accepted, other rejected. When the regulation is first published as a final rule it appears in the Federal Register along with a summary of the comments and FDA's responses and explanations, called the preamble. Preamble's have legal standing and are worth your while to read and understand.

Once a year the regulations and associated amendments, but not the preambles, are published in the Code of Federal Regulations, Title 21. 21 CFR, Parts 1-99 are regulations that apply to devices, drugs, and biologics. Parts 800-1299 are regulations that apply only to devices. If you work in clinical research, you should become intimate with Parts 50, 54, 56, 812, and 814.

Device Classification—point of entry
Devices are as diverse as toothbrushes to heart valves, or sunlamps to breast implants. It would be unreasonable to regulate all devices the same way. Wrapping your mind around a country's approach to device regulation is challenging. The point of entry is to first learn how that country classifies devices. All countries classify devices by history or risk, and then regulate the devices differently depending on its classification. In the States, devices are classified as Class I—General Controls, Class II—Special Controls, and Class III—Premarket Approval.

Class I devices have a reasonable assurance of safety and effectiveness if manufactured under current good manufacturing practices. Approximately 74% of the Class I devices are exempt from the premarket notification process (i.e., 510k clearance). These exemptions are listed in the classification regulations of 21 CFR and have been collected together in the Medical Device Exemptions document.

Class II devices have a reasonable assurance of safety and effectiveness if manufactured under current good manufacturing practices and whatever special controls deemed necessary by FDA, such as performance standards, postmarket surveillance, patient registries, guidance documents, or evidence of efficacy from a well-controlled clinical study.

Class III devices are devices purported or represented to be for a use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health and there is not sufficient information to establish a performance standard for reasonable assurance of safety and effectiveness.

Intended Use, Indications for Use
Let's say you are developing a device that is new to your company. Your first concern is to identify its classification, because all other regulatory requirements will stem from there. But the classification will depend on a few more variables you'll have to fix before you can make that determination.

Intended Use
The first decision is to decide on the intended use for the device. In a market-driven company we probably have an indication (customer need) looking for a device, but in technology-driven companies it is common to have a device looking for an intended use. Think in terms of an active verb: do you intend to ablate tissue, vibrate cells, stimulate neurons, fix body parts, take images, or measure impedance? Deciding on your intended use for a device is the first step in determining its classification.

Indication for use
The next step is to decide on the disease or condition you plan to diagnose, cure, mitigate, treat, or prevent. Think in terms of diseases and conditions to which the intended use can be applied. You might ablate tissue in order to prevent tumor growth, you might vibrate cells in order to intercept a seizure, you might fix the spine in order to prevent curvature or treat scoliosis, and so on. The intended use may have many applications in medicine, i.e., there may be many diseases or conditions to which it can be applied.

Some indications will cause your device to be classified higher than other indications. For example, if you say your device will diagnose breast cancer it is going to be a Class III device, but if you say it is a adjunct test for the diagnosis of breast cancer it will be a Class II device. If you indicate a device that exposes to body to magnetic waves as a treatment for HIV it is going to be a Class III device, but if you indicate that magnetic waves help activate the immune system to viral load, it may be a Class II de novo.

Think of your device as consisting of two parts: 1) the physical device, and 2) its indications for use. If you are a start-up firm, choose an indication for use for which it is easy and inexpensive to get FDA clearance. Go after the harder, and more profitable, indications for use after you have experience and cash flow.

How to determine classification
Go to FDA's product classification database and search for a part of the device name or, if you know the device panel (medical specialty) to which your device belongs, go directly to the listing for that panel and identify your device and the corresponding regulation.

It may sound simple to find your device, but it isn't. The classification database does not have a fuzzy search engine; you will find only what you ask for. Suppose you have a radio-frequency ablation device. A search for "radio frequency ablation" turns up nothing, a search for "RF ablation" turns up nothing, finally a search for "ablation" brings up twelve records: one is a mapping instrument to plan the ablation, four are for cardiac atrial flutter, one is for endometrial ablation, one for urological ablation, one—for treatment of varicose veins—is grandfathered in as a pre-amendment device, two are low-energy devices for general soft tissue ablation, one uses ultrasound as a high energy source, and one uses liquid nitrogen for cosmetic surgery (like removing moles).

It is useful to note is that the primary tissue (think disease or condition) being ablated dictates which device panel reviews the device, and the energy intensity (high or low) as well as the newness of the technology dictates its classification. Unfortunately, we still don't know how our RF-ablation device is classified.

Device classification panels
FDA has classified and described over 1,700 distinct types of devices and organized them in the CFR into 16 medical specialty "panels". For each of the devices classified by the FDA the CFR gives a general description including the intended use, the class to which the device belongs (i.e., Class I, II, or III), and information about marketing requirements. Your device will presumably meet the definition in a classification regulation contained in 21 CFR 862-892.

A search for "RF" in the product classification database is more useful. We find seven devices, one is a Class III device for RF/microwave hyperthermia for cancer treatment—sounds like a good match and finally we know the class and regulatory status of our device and indication.

Let's discuss the product code. The product code, together with the product name, uniquely identifies a category of devices for FDA and is a useful way to find related products. If you go to the PMA database and search on the product code LOC, you will find 27 PMA submissions or amendments. Here you will find some useful information, such as the manufacturer of the devices, when they received clearance, location of the manufacturing facilities, which advisory panel reviewed the PMA, and more.

Notice the absence of a Regulation Number? While FDA may say: "Your device should meet the definition in a classification regulation contained in 21 CFR 862-892," the truth is that it can take years before FDA assigns a regulation number to a new product category.

510(k) or PMA
The point of classification is to determine the pathway to FDA clearance. You don't have a choice in the matter, unless you want to revise the indications for use. To summarize it simply:
[ ] Class I—74% are exempt from requiring FDA clearance, the remainder need a 510(k).
[ ] Class II—requires a 510(k), which is a type of FDA submission in which you argue that your device is substantially equivalent to another device which was on the market prior to May 28, 1976.
[ ] Class II de novo 510(k)—a Class III device that is a new technology of low risk; for example exposing the hands to a magnetic field for immune system stimulation. New technologies are automatically Class III devices, but the manufacturer can petition FDA for a down-classification to Class II. The difference is the 510(k) requires de novo (from the beginning) evidence of safety and effectiveness, rather than evidence of substantial equivalence, because there is nothing to be equivalent to.
[ ] Class III—requires pre-market approval (PMA).

The BIG question—do you need a clinical trial?
The question we've been trying to answer with all of this is whether or not we need to do a clinical trial in order to get FDA clearance. The answer is:
[ ] No, if you have a Class I device.
[ ] Maybe, if you have a Class II device. About 10% of 510(k)s require clinical trials in order to support the argument of substantial equivalence.
[ ] Yes, if you have a Class II de novo device.
[ ] Yes, if you have a Class III, PMA device.

If you liked the whitepaper, take the workshop
The objective of the workshop is to learn the basics of FDA device regulations and how to determine if you need a clinical study in order to get FDA clearance. Sign up at registration.

This is an introductory workshop and focuses on US regulations. A complimentary workshop focusing on European regulations is also available.

You will receive, we wil discuss
[x] PowerPoint slides.
[x] A three-hour presentation.
[x] Discussion of the types of 510(k).
[x] Difference between 510(k)s and PMAs.
[x] How to take advantage of the Mohan memorandum.
[x] Distinction between guidance documents and standards.
[x] Supporting handouts, flowcharts, and graphic presentations.
[x] A complimentary US/ISO Adverse Event mousepad/notepad (by mail).
[x] A 30-minute quiz to reinforce your learning experience.
[x] CEUs and certificate of attendance.

Who should attend
[x] Anyone new to medical devices.
[x] Anyone new to medical device clinical trials.
[x] Anyone needing to know about medical device regulations.

Presenter
Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration for US Workshop
The three-hour workshop will be presented on Tuesday, 06 July 2010, at 10:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Date, time, registration for EU Workshop
The three-hour workshop will be presented on Wednesday, 1 July 2010, at 1:00 pm Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Learn the world discount
Register for both workshops and get $100 off! Enter the coupon code SUMMER at check-out.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

Reporting Study Deviations: US and ISO

A Whitepaper and Workshop by Nancy J Stark, PhD Wednesday, 30 July 2010, 11 AM Central; or OnDemand soon after. Reading someone else's copy? Opt-in for whitepapers to get your own. In this whitepaper I want to discuss the concepts of study deviations, violations, non-compliances, and amendments; and to compare the US and ISO positions with regard to reporting. When I say ISO, I mean ISO/FDIS 14155 "Clinical investigation of medical devices for human subjects—good clinical practice" (2010) which may be purchased from the International Standards Organization in Geneva. When I say US, I mean 21 CFR Part 812 plus a collection of FDA guidances and IRB voluntary standards. A poll—how many deviations do your colleagues make? Maybe you'd like to compare your perceptions to your colleague's. Answer poll question 18, "How many total deviations do you think will occur in a typical device study of 100 subjects, 50 case report forms per subject, and 5 investigative sites?" and then see what your colleagues had to say. The one hundredth person to answer the poll will receive an Adverse Event Notepad. Who deviates? Who amends? Investigators deviate, sponsors amend. It is the nature of 'sponsored' research: the firm paying the bills gets to design the study the way they want within the limits of regulatory and ethical boundaries. The difference between an amendment and a deviation is timing: did the investigator get permission prior to making the change, or did they make the change and then go to confession.   Sponsors may, themselves, contribute to deviations. Sponsors do incredible things such as: 1) writing protocols with such tight specifications they cannot be reasonably followed, 2) authorizing changes verbally, but not following up in writing, 3) approving changes they have no authority to approve, 4) inadequately training the study staff, 5) not insisting on IRB or EC approval or notification, 6) not insisting on FDA approval or notification, or 7) changing the device—such as it's configuration, formulation, materials, or software—without prior approval or notification, 8) selling devices without FDA clearance (tantamount to conducting a study without approval), 9) trying an unapproved device on a few patients to see if the design is right, or 10) a host of other things I haven't thought of yet. Regulatory definitions ISO/FDIS 14155 is clear on what it means by a deviation. Section 3.14 defines a deviation as an "instance(s) of failure to follow, intentionally or unintentionally, the requirements of the [protocol]." A violation is not defined. And the only reference to a non-compliance is in regard to subjects not complying with requirements stated in the informed consent (Section 8.2.4.5.q—Routine on-site monitoring visits.) ISO/FDIS 14155 has no definition for amendment, but it can be deduced that it means any intentional change made to the investigator's brochure, protocol, case report forms, informed consent form, or other study documents; that the change must have the approval of the sponsor and investigator, and be noticed to the EC and regulatory authorities. (Section 6.5.1.) Part 812 has no definition of deviation, but it does say that the investigator is responsible to keep a log of deviations from the protocol (Part 812.140(a)(4)). Emergency deviations taken to protect a subject are reportable to the sponsor and reviewing IRB within 5 working days (Part 812.150(a)(4)). All other deviations require prior approval by the sponsor and possibly the IRB and FDA, and we usually consider these to be amendments. The only reference to a noncompliance is in regard to good laboratory practices. The IRB's view It's useful for sponsors to understand the IRB's point of view, because we are so concerned with our investigator's compliance to their requirements. It's mostly that their use of words is different. They think in terms of unanticipated problems, where a problem can be anything from a shortage of test tubes to malfunctioning equipment. In the short term, they want to know about everything that is unanticipated; the anticipated events can go in the annual report.   The IRB doesn't think in terms of deviations so much as unanticipated problems. And they merge the issue of adverse events with problems that are anticipated or unanticipated; in other words an adverse event is one more type of problem. Industry definitions It really isn't that hard. The ultimate goal is that no one gets to act independently, or make changes to the study plan, i.e., the protocol, investigator's brochure, case report forms, informed consent form, and any other critical study documents, without everyone else's approval. Here are definitions the industry has come to use: [ ] Deviation—a failure to follow the study plan. A deviation that occurs repeatedly should probably become an amendment. [ ] Violation—a failure to follow the study plan in such a way that subject safety was in jeopardy. [ ] Non-compliance—a failure to follow a regulation or IRB requirement. [ ] Amendment—a change to the study plan after obtaining the necessary permissions. [ ] Unanticipated—not identified in the study plan.

And what about reporting Only deviations and violations (and adverse device effects) have to be reported, since amendments already have approval. Time frames differ depending on IRB, country, the event's effect on subject safety and data integrity, and what you said in the protocol. The protocol is king, it governs your study. A wise monitor once said to me: "You can do anything, if you put it in the protocol." For ISO: The monitor is expected to identify deviations, discuss them with the investigator, and list them in the monitoring report (Section 7.2.4.5.a.) The sponsor is expected to list the deviations in progress reports as requested by reviewing ECs and regulatory authorities (Section 8.2.3.f). Investigators that cannot be compliant may need to be excused from the study (Section 7.1.1.) For FDA: The US is different from the rest of the world in that we have a risk classification system for clinical studies. The rules are different for non-significant risk and significant risk studies, and this system is unique in the international community. For significant risk studies, the investigator is expected to keep a deviation log (Part 812.140(a)(4) and report deviations to the sponsor (Part 812.150(a)(4)). The sponsor is expected to take steps to bring the investigator into compliance either by withholding shipment of additional devices or by reporting the investigator to FDA. These requirements do not apply to non-significant risk studies. For US IRBs: The rules vary from IRB to IRB, but if the board follows the OHRP guidance, unanticipated problems should be reported in the short term (my phrase) and anticipated problems in the annual progress report. Workshop learning objective The objective of the workshop is to explore the US and ISO definitions and reporting requirements in more detail, using practical examples to apply the rules, and reviewing warning letters to see how we have all gotten into trouble. You will receive [x] PowerPoint slides. [x] By popular demand, a three-hour course. [x] Office of Human Research Protections (OHRP) "Guidance on reviewing and reporting unanticipated problems involving risks to subjects or others and adverse events" (Jan07). [x] FDA "Information sheet guidance for IRBs, clinical investigators, and sponsors; FDA Institutional Review Board Inspections" (Jan06). [x] FDA "Changes or modifications during the conduct of a clinical investigation; final guidance for industry and CDRH staff" (May01). [x] FDA "Deciding when to submit a 510(k) for a change to an existing device" (Jan97). [x] A 30-minute quiz to reinforce your learning experience. [x] CEUs and certificate of attendance. Who should attend [x] Anyone monitoring a device trial. [x] Anyone sponsoring a device trial. [x] Investigators for device trials. [x] Regulatory professionals who prepare submissions to FDA. [x] Managers who sign-off on clinical trials. [x] Executives who are planning the future of their companies. Presenter Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com. System requirements [x] Personal computer. [x] Internet Access. [x] Telephone. Date, time, registration The three-hour workshop will be presented on Wednesday, 30 June 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration. Best Regards, Nancy J Stark, PhD President, Clinical Device Group Inc

The Difficulties of Good Data Management

A Whitepaper by Dr. Nancy J Stark
Reading someone else's copy? Opt in to whitepapers and get your own.

Let's define a mid-sized device study as 100 subjects, 50 pages of paper case report forms per subject, and an average of 10 fields per page. Device sponsors are always surprised to hear that data management for such a study will require in the neighborhood of 2500+ hours. So what's all the time about?

How it is supposed to work
In a perfect world, data management would happen by the seamless convergence of data collection and database design. I'll discuss a paper-based model first, because that's what most start-ups use and it is easier to understand. Then I'll look at some electronic data capture (EDC) variations.

...Data collection
Data collection begins with defining what data to collect in order to support what you want to show. In other words, start with your envisioned indications for use, then determine how to measure device performance to that indication; the parameters you measure are called the endpoints. 'Endpoint' is an old term that used to mean the end of data collection. Today it means the pivotal data point that demonstrates product success or failure.

You progress to a set of case report forms that are easy for the Form Filler (at the study site) to fill out and error-proof for the Data Enterer (at the data management center) to enter. The case report forms should collect all the data that are necessary to support or refute the indication for use under study.

...Data verification
The case report form data is verified against the source files (medical records) by a monitor who is independent of the Form Filler. When the sponsor and investigator are separate parties, the monitor works for the sponsor and independence of the Form Filler is assumed. When the study is sponsored by the investigator (an investigator-sponsored study), the monitoring function should be outsourced to a third party who has no financial interest in the outcome.

...Handling test reports
Much of the data will be presented in the form of reports from, say, gastroenterologists or interventional radiologists. Statisticians can't work easily with the comment data found in reports. You'll need to develop questions that capture the essential elements of these reports in order to have usable data for analysis. You might have a series of questions, such as: "Is there any sign of cancer: yes, no, unsure." "What is the widest dimension of the cancer (enter 0 for no or 99.9 for unsure): __.__ mm." etc.

...Other data sources
There will likely be other sources of data too. Digital data may be recorded directly from the device. These data might be impedance, frequency, milliseconds, watts, or other parameters of device performance. Or these data might be measurements taken from the subject such as resistance, oxygenation, pH, or blood pressure.

Clinical laboratory data may be recorded on a laboratory information system (LIMS). These data may include analyst concentrations like glucose or potassium or cholesterol levels; or enzymatic levels such as alanine transaminase; or red, white, or plasma cell counts in the blood.

...Data dictionary and map
Next it is time to finalize the data dictionary and data map. The dictionary defines each data element. The definition may be self-evident but sometimes a more lengthy definition is required, perhaps the CT with contrast means a cat scan with barium contrast medium. The definition includes the data type, range of accepted values if any, and maps the data to its source. The dictionary and map aren't just for convenience. They make up part of the meta-data that enables the reconstruction of events at a future time, should that be necessary.

Using the correct data type is very important if you want calculations to run properly downstream. For example, to calculate the subject's age at the time of consent you would subtract the birth date from the consent date. If we erroneously enter the consent date as text, the calculation will return an error. It can be easily fixed, but it will probably cost half a day in labor.

...Database design
Meanwhile, back at the data management center, the Database Designer designs a database uniquely built to receive the data from the various sources of data. The structure of questions on the case report form dictates exactly the structure of the database. If the question says: "How many apples did you eat today?" the database must receive integer data. If the question says: "What was your primary source of protein for lunch? Select one." The database will have a drop-down box that allows the Data Enterer to select one option from a predetermined list. If the question says: "Which of the following vegetables did you eat today? Check all that apply," a related table will be designed that allows several answers to be linked back to a specific subject.

In addition, remember the digital data that is coming in from the device? The database must be designed to accept these data when they are electronically imported and to automatically link the data to the correct subject. The same holds true for any clinical laboratory data that will be directly imported.

Finally, a set of management and outcomes reports will be coded. Management reports will enable managers and sponsor to follow the progress of the study without revealing study outcomes. A typical list of manager's reports includes: [1] Data entered by subject, [2] Data queries by subject, by site, by monitor, [3] Missing data, [4] Adverse events, and [5] Data received but not yet entered. One type of summary report is shown below. Here, each subject is represented by a row, and the case report forms make up the columns. The forms are color-coded to show if the data are entered (blue), missing (gray), outstanding due to queries (red), or received but not entered (yellow).

Outcomes reports might consist of, say, [1] time to an event, [2] number of events at day 14, [3] correlation of diagnosis with gold standard, or [4] any other calculated result.

...Database validation
To validate the database, three or four sets of faux patients are entered into the database. The phony data are entered, reports are run, and the answers are checked against manual calculations. In this way it can be confirmed that all the tables are synchronized, edit checks are firing properly, correct data types are being accepted as specified in the data dictionary and map (below), calculated fields are functioning, and database queries are working.

...Version control
The final touch to the database application is to invoke a version control system. Once the design of the database is validated, the Access or Excel file is 'checked in' to a library such as Microsoft Sharepoint or SourceSafe. Then, whenever someone wants to make a change to the code they check it out of the library, make their changes, and check it in again. The version control software will automatically increment the version number, record who made what changes, and provide a space for notes.

...Convergence: merging data and database application
After the database application is validated it is ready to receive the 5000 pages of case report form data from the mid-sized study described above. This involves entering 50,000 data points! In our perfect world, our easy-to-enter forms are forwarded to the data management center where the Data Enterer enters the data without error. The data may also be re-entered, verified, or reviewed by a second person to improve data quality.

Once all data have been entered and reviewed, edits run, and those very expensive queries resolved (see below), there should be no missing or illegible data and no outstanding data queries. The digital data from the device are forwarded and match exactly with the patient numbers when uploaded. Ditto for the laboratory data.

...Data audit trails and other Part 11 issues
As data are entered into the database an independent, but corresponding, record is kept of what data are entered or changed, when, and by whom. This creates an audit trail of the data (as opposed to version control of the database application). Affordable audit trail/Part 11 add-ons are commercially available for both Access and Excel (still the most popular application for data management). The audit trails will track every entry and every change to data fields, generating a complete history of data entry and data changes.

...Data validation and lock
Earlier we validated the database, confirming the fields were the correct data type, which related tables were properly linked, and reports were accurate. After data entry, we validate the data itself. I like to print a report that 'looks' like a case report form. I print out, say, 10% of the forms and manually compare them to the case report forms used for input. And I print out a report of endpoints. A common level of error acceptance is 0% for pivotal endpoints and 0.5% for other fields. Finally, the data can be locked, imported into SAS, reports can be run, statisticians can analyze, and all is right with the world.

Electronic Data Capture
Viewing it simply, in a paper-based system the data are transcribed onto case report forms by the Form Filler at the study site. After source verification, the data are forwarded to the data management center for data entry by a Data Enterer. In electronic data capture (EDC) the validated database is uploaded to a server and study staff are given access via a password and secure connection. Rather than fill out a paper form, the Form Filler is also the Data Enterer. This is where you'll have a cost savings because the work isn't duplicated and a Form Filler/Data Enterer is entering data directly from the source files.

EDC systems are a worthwhile investment if your company expects to do many trials with similar designs and your investigators are comfortable with computers and applications.

How it usually works
Unfortunately, life is rarely a straight-forward path, and we often begin in the middle. The numbers of things that can go wrong are too many to enumerate. But here are a few likely problem-makers.

...Questions change
It seems so minor, changing a question on the case report form so it makes more sense to the Form Filler. But if you change the data type, it might be hard to merge data for that question from before and after the change. Even worse, you are looking at a couple of hours of database re-design and re-verification.

...Differing subject ID numbers
How can it be? Subjects are numbered 1-100 in the database, but 20100607.1-20100607.100 from the laboratory. As humans, we can see it is a date followed by a number, but our database does not understand. Another half-day is lost learning there is a problem, identifying the problem, and fixing the problem.

...Adverse events
Adverse event data can require a lot of time to manage. The event must be followed until it is resolved or stabilized, and that may not happen for several months. Ongoing adverse events keep the database open and require continuing updates for an indeterminate length of time. Ongoing reports to Database Monitoring Committees or Clinical Events Committees also demand extra time.

...Missing data
Unfortunately, some forms will come in with missing values. When a value is missing, i.e., a question is unanswered, the integrity of the data are compromised. If the missing value is a pivotal endpoint, the Form Filler will be asked by data query to track down the missing data. If the value is no longer available, (let's say you wanted the patient's temperature immediately after the procedure), the statistician may be able to guess at a defensible value for the missing data, but it is still a guess.

...Data queries
Paper case report forms are written in handwriting. In spite of the best monitoring and source verification, some illogical or illegible data will slip through. "Now, let's see", thinks the Data Enterer, "is that a six or a zero?" A data query is sent to the monitor, who sends it to the Form Filler, who looks up the correct answer in the source file and sends it back to the monitor, who sends it to the Data Enterer. This is good for 15 minutes of Data Enterer time, 15-30 minutes of monitoring time, and 30 minutes of Form Filler time. Not counting the Form Filler, we can assume $125 per data query. If there is one data query per subject, that would be $62,500!

Thankfully, in the EDC world, illegible handwriting is not an issue for the data manager as the entry has already been reviewed by the site. Typically, in EDC studies, less time is spent dealing with handwriting and missing value queries and effort can be focused on more complex queries.

...Data arrival
When data are coming in from multiple sources, it doesn't always arrive at the same time. You may have all the device data for subjects 1-37, the paper case report forms for subjects 1-30 except for subjects 3 and 23 which were held back, and no laboratory data. You'll need ongoing management reports to show what data has been received for what subjects, and what data the monitors should be tracking down at the site.

Communication
Throughout all of this, communication will be recorded by email messages. Messages should be written clearly and with detail. All phone conversations are summarized with a list of action items. When referring to a database or spreadsheet, use its name and version number. Communication is not only meant for the immediate reader, it is meant to be meta-data (data about the data) which can serve to reconstruct events at a point in the future. For contractors this is especially important; billing issues are usually resolved based on written communications.

Periodically, all the messages are selected and printed (memo style) to Acrobat Writer. The long pdf file is bookmarked with relevant tables of contents, burned to a CD, and stored as a permanent part of the technical file.

Not just CDG's numbers
I used my own data, of course, but I also called upon the goodwill of several friends to assemble the hours estimate below. A perfectly designed, perfectly executed study will not come with free data management.

How Clinical Design Group can help
Building a database, validating the database, invoking audit trails, rendering the database Part 11 compliant, entering and importing data, validating the data, exporting the data for SAS analysis, and documenting communication are all part of the data management services that CDG offers. Whether you want a paper-based system or an electronic data capture system, CDG has the capabilities and experience to help you.

Do you need all of these services, only part of them, or consulting to help you do it yourself? You can contact Clinical Device Group for help. Here are some of the Network Staff and resources who we have at to help you.

...Meet Wessam Sonbol, Database Designer
Wessam Sonbol is the President of Clinical Systems Consultants Inc. Mr. Sonbol graduated from the University of Minnesota’s Institute of Technology with a degree in computer science. Throughout his career he has held positions at Eminent Research/PPD, American Medical Systems and Sorin Group. He developed a global database with which he gathered data from hospitals all over the world to review cardiovascular diseases and understand the demographics of different causes. Wessam also developed http://www.tctmd.com, an informational website for doctors focusing on Trans Catheter Therapeutics; and Global View, a post-market eRegistry tool used by many organizations such as St. Jude and J&J.  He also developed studies using Oracle clinical, Clindex, ERT and Rave and designed a MS Access 21 CRF 11 compliant database. 

...Meet Michelle Secic, Biostatistician
Michelle Secic is the President of Secic Statistical Consulting, Inc. where she works on a variety of medical research projects.  She aids companies around the world with the statistical aspects of their research from small projects to large clinical trials involving drugs or medical devices. She received her Master of Science degree in applied statistics in 1990.  She worked at the Cleveland Clinic Foundation from 1990 through 2001, when she left to continue expansion of her own consulting company.  She authored a book in 1997 titled "How To Report Statistics in Medicine", published by the American College of Physicians. The book was translated into Chinese and published in China in 2002; the second edition was released in 2006.

...Meet Dr. Robert Thiel, Biostatistician
Robert Thiel, PhD is the President of Thiel Statistical Consultants. Dr. Thiel has degrees in physics, clinical counseling and psychometrics. He is an expert in the analysis of IVD data for the Medical Device Industry with more than 75 510K and 5 PMA approvals. He has published papers in the areas of free PSA, breast cancer, ovarian cancer, liver disease and multivariate analyses as applied to sports (baseball and basketball).

His current interests lie in the area of Bayesian statistics, bootstrap and permutation test methodology, and the application of these methods to small sample trials.

...Meet Clindex, a web-based EDC system
Clindex (Fortress Medical Systems LLC, MN) offers a Clinical Data Management System, Clinical Trial Management System, and EDC System in one integrated solution. The software is designed for use with medical devices and diagnostic products (and okay, with pharmaceutical trials; but those of you who know me know I don't do drugs....) Clindex is used from start-up firms to Fortune 500 companies. It has been used in hundreds of clinical studies, international studies, and studies that supported FDA marketing applications. The FDA has inspected numerous companies using Clindex with no feedback of any findings or deficiencies.

I look forward to hearing from you!

Best Regards,

Nancy J Stark, PhD
President, Clinical Device Group Inc
773-489-5706
cdginc@clinicaldevice.com

Why Do Non-Inferiority Clinical Studies?

A Whitepaper by NJ Stark and e-Conference by Dr. Robert Thiel Learn more Wednesday, 7 July 2010, 11 AM Central; or here OnDemand soon after. Reading someone's elses copy? Opt-in for whitepapers to get your own. I read an interesting comment in a press release this morning. The CEO of Spectranetics said: "Our physician customers prefer randomized, controlled studies to assist them with their clinical decisions...." and "Our clinical trial program ... demonstrates our commitment to evidence-based medicine." Every book or guidance document I read has a different way of categorizing clinical studies. One obvious categorization for medical devices is by whether or not you are doing a single-group (single-arm) study with no comparator, or whether or not you will compare your device to another. My experience is that most device studies are single-arm designs so I read the Spectranetics press release with a loud hurrah. A poll—what's everybody else doing? What is the most common category of clinical trial your company conducted last year? [a] Single arm. [b] Superiority. [c] Equivalence. [d] Non-inferiority. Answer poll 17 to compare yourself to others. Be the 100th person to answer the poll and win a free Adverse Event note pad. Non-inferiority studies use smaller sample sizes In any comparative study you want to show whether your investigational device is better than, the same as, or no worse than the competitor. If you will be filing a 510k, you might think that you need to be the same as the comparator in order to support the argument of substantial equivalence. It makes sense. The difficulty arises when you calculate the sample size. Sample sizes are calculated based on the difference between the average values of an endpoint. The greater the difference between your device and mine, the fewer the number of subjects you'll need to show it. As the difference between your device and mine gets smaller, the sample size gets larger and larger. As the difference becomes infinitesimally small, i.e., the devices become equivalent, the sample size skyrockets to infinity. Enter non-inferiority. Instead of showing that two devices are the same, a clever FDA statistician named Blackwelder looked at things differently and developed a strategy called "Proving the Null Hypothesis". He figured that if we stopped trying to prove the hypothesis and reject the null, and instead rejected the hypothesis and proved the null, we could accomplish the same thing as an equivalence trial but with a much smaller sample size. Blackwelder's ground-breaking paper was published in 1982. FDA's new guidance document In point of fact, device manufacturers have been doing non-inferiority studies for years; FDA kindly points out the opportunity every time a manufacturer proposes implementing a superiority trial. It is just as unethical to do an unnecessarily large study as it is too do too small a study. Recently, FDA issued a draft guidance document titled "Guidance for Industry - Non-Inferiority Clinical Trials" (Mar2010). The guidance was issued by CDER and CBER because non-inferiority trials require active controls rather than placebos—something new for the drug world. We device people are familiar and comfortable with active controls (who would use a placebo heart valve?), and there is much a good biostatistician like Robert Thiel can teach us with regard to medical devices and diagnostics. What device companies already know The guidance document points out some important "issues" in implementing non-inferiority studies. If you've designed non-inferiority studies before, you have probably already encountered them. [1] You have to know the comparator's performance for your 'pivotal' endpoint. You might learn this from the literature, benchtop data, animal data, or even data gathered at your own expense on the comparator device. [2] You have to judge the investigational device's performance for the 'pivotal' endpoint based on data such as benchtop data, animal data, or data from similar, commercial devices. [3] Non-inferiority really means "not too inferior", and how inferior is too inferior must be determined. You should plan on plenty of pre-protocol discussion over this topic. [4] The study design must be able to detect a difference if there is one. [5] The need to show a lack of difference can lead to a lack of incentive to study excellence, i.e., sloppiness. I personally take issue with this statement, FDA, but I'll let it go.

Motivate Your Study Staff: Give an Adverse Event Note Pad/Mouse Pad The Adverse Event note pad is a graphical way for study site staff to categorize adverse events. Starting at the center, they choose the characteristics in a pie-wedge that best describe the event. The outer ring identifies the event by type. ISO definitions, accepted by FDA, are provided on the right. The tool helps study staff think their way through to the reporting requirements described in the protocol. Read more. Learn more: take the e-conference The objective of the e-conference is to learn more about the historical pitfalls in the design and execution of non-inferiority trials and how to avoid them. Addendum: Brief Comments on Missing Data Let's shift gears and speak for a minute about missing data. The clinical trial has not yet been conducted where there hasn't been at least some missing data: the subject can't remember it, the study staff forgot to record it, the dog ate it, and the statistician is leftout with it. There are three basic kinds of missing data: [1] Data may be 'missing completely at random', meaning the probability that an observation is missing is unrelated to its value. For example, if a subject missed a follow-up visit because of jury duty, the data would be missing at random and we could impute the missing values. [2] Data may be 'missing at random' but not completely at random. For example, people who are depressed might be less inclined to report their income than others. If we can account for the variable depression, we can impute the income value. [3] Data may be 'missing not at random'. For example, if we ask people to report their income, low income people are less likely to respond. The income data is definitely not missing at random, it is missing specifically for a particular group of people. We can't simply impute the value, an algorithm must be developed. A good study design has a plan (called a statistical analysis plan or SAP) that, among other things, determines beforehand how missing data will be identified and handled. Dr. Thiel will take a few final moments to discuss this important, but neglected, issue. Dr. Thiel will discuss [1] What resources are needed to design and execute a non-inferiority trial. [2] What the FDA expects to see for a trial of this type. [3] Design problems with active-control (non-inferiority) clinical trials. [4] Statistical issues associated with non-inferiority clinical trials. [5] How the results of non-inferiority clinical trials are interpreted. [6] The all-important margin of error. [7] An addendum: Handling missing values. You will receive [x] PowerPoint slides. [x] An interpretation of the guidance document. [x] Practical examples to learn from. [x] The expertise of a prominent biostatistician. [x] Chance for Q&A. [x] CEUs and certificate of attendance. Who should attend (no, you do not need to be a statistician) [x] Clinical research professionals who design clinical trials. [x] Regulatory professionals who report clinical data. [x] Statistical professionals who analyze clinical data. [x] Managers who sign-off on clinical trials. [x] Executives who are planning the future of their companies. Presenter Dr. Robert P. Thiel has degrees in physics, clinical counseling and psychometrics. He is an expert in the analysis of IVD data for the Medical Device Industry with more than 75 510K and 5 PMA approvals. He has published papers in the areas of free PSA, breast cancer, ovarian cancer, liver disease and multivariate analyses. His current interests lie in the area of bootstrap and permutation test methodology and the application of these methods to small sample trials and Bayesian analysis as applied to diagnostic clinical trials. Dr. Thiel can be contacted at rpthiel@thielstatcon.com. System requirements [x] Personal computer. [x] Internet Access. [x] Telephone. Date, time, registration The 90-minute e-conference will be presented on Wednesday, 7 July 2010, at 11:00 Central Time. Event materials will be distributed the day before the e-conference. Sign up at registration. Best Regards, Nancy J Stark, PhD President, Clinical Device Group Inc Click here to receive CDG news via our XML/RSS feed Follow us on Twitter